Women account for nearly one-half of new HIV-1 infections worldwide, including the majority of infections in Africa. Heterosexual intercourse is responsible for most HIV-1 transmissions to women, and the majority of HIV-1 infected women are of reproductive age. Biologic and epidemiological studies have suggested that the use of hormonal contraception or pregnancy may influence susceptibility to HIV-1, infectivity of HIV-1, and progression of HIV-1 disease, but the relationship has not been consistent across all studies and considerable variation in study quality could explain differences between studies. Understanding the relationship between contraception, pregnancy, and adverse HIV-1 outcomes is a topic of public health importance, because effective family planning is central to initiatives to improve the health of women and children worldwide. We propose to explore the effect of hormonal contraceptive use and pregnancy on HIV-1 acquisition in women, HIV-1 transmission from women to men, and HIV-1 disease progression in women with chronic and primary HIV-1 infection through secondary analysis of data collected as part of a prospective study among 3408 heterosexual HIV-1 serodiscordant couples from 7 African countries (the Partners in Prevention HSV/HIV Transmission Study). This study thus offers a unique repository of high-quality, prospectively-collected epidemiologic data, and advantages of our approach include the large multinational sample size, the unprecedented opportunity to directly explore female-to-male HIV-1 transmission risk, ability to quantify exposure behaviorally and biologically (plasma and genital HIV-1 levels in the infected partner), and the quality of data. We will: 1) assess the effect of hormonal contraception on risk of HIV-1 acquisition in women and transmission from women to their male partners, 2) assess the relationship between pregnancy and risk of HIV-1 acquisition and transmission, 3) among women with chronic infection, assess the effect of contraception and pregnancy on risk of HIV-1 disease progression (CD4 decline to <200 cells/mm3, initiation of antiretroviral therapy, or death) and among women with incident infection, determine the effect of contraceptive use and pregnancy on set point plasma HIV-1 levels and early CD4 counts, and 4) assess whether contraception or pregnancy are associated with higher plasma and genital HIV-1 RNA concentrations, which could explain higher infectivity and faster disease progression. PUBLIC HEALTH RELEVANCE: During the past 15 years, a number of studies have suggested that the use of hormonal contraception or pregnancy may influence women's susceptibility to HIV-1, the transmission of HIV-1 from women to men, and progression of HIV-1 disease in women, but the relationship has not been consistent across all studies and considerable variation in study quality could explain differences between studies. We will explore the effect of hormonal contraceptive use and pregnancy on HIV-1 acquisition in women, HIV-1 transmission from women to men, and HIV-1 disease progression in women with chronic and primary HIV-1 infection using data collected as part of a prospective study among 3408 heterosexual HIV-1 serodiscordant couples from 7 African countries. The results of the proposed projects will fill critical knowledge gaps that are key to the health of women worldwide and are urgently needed to develop clear risk-reduction messages for women using contraception and to provide the safest contraceptive options to women with and at-risk for HIV-1.